Management of refractory IBD starts with excluding patients who don't have it

A majority of patients with inflammatory bowel disease (IBD) fail to respond, have an inadequate response or lose response to standard medical therapies. Although some patients may be truly refractory to medical treatment, in others, symptoms may be unrelated to the underlying IBD, according to Edward V. Loftus Jr. M.D., director of the IBD clinic at Mayo Clinic's campus in Rochester, Minnesota.

"The problem is that IBD symptoms are neither sensitive nor specific — the gastrointestinal tract can only express its displeasure in so many ways," he says. "A common mistake is to automatically assume that increased symptoms in a patient with established IBD are due to the disease. That's often not the case, and patients should always be tested before ratcheting up drug therapy."

Refractory IBD management

Dr. Loftus says the first step in managing refractory IBD is to consider and exclude the following:

Enteric infections

As many as 20 to 30 percent of IBD patients experiencing flares may have concomitant C. difficileinfection (CDI), and all patients with worsening symptoms should routinely undergo a stool test for CDI, such as toxin EIA, or a molecular polymerase chain reaction test.

Cytomegalovirus (CMV) infection is also not an uncommon finding in IBD. The virus, latent in a majority of immune competent people, can be reactivated in the context of colonic inflammation and immunosuppressant therapy. Although the exact role of the virus is controversial, evidence suggests that CMV is involved in the resistance of ulcerative colitis to immunotherapy and that patients with a high density of CMV inclusions in colonic tissue — five or more inclusions per biopsy fragment — benefit from antiviral therapy.

Celiac disease

Having IBD doesn't rule out the possibility of celiac disease, which should be considered in patients who seem resistant to standard treatment.

Lactose or fructose intolerance

Large population studies have found a significantly higher prevalence of carbohydrate malabsorption among patients with IBD compared to healthy controls.

Irritable bowel syndrome (IBS)

Although clinicians are often hesitant to diagnose irritable bowel syndrome in the presence of IBD, such a diagnosis is possible when there is no active inflammation, Dr. Loftus says.

Bile acid diarrhea and small intestine bacterial overgrowth (SIBO)

Small intestine bacterial overgrowth is common in Crohn's disease patients who have undergone ileocecal resection or have strictures, fistulas or reduced intestinal motility. Ileal resection and Crohn's disease itself also prevent bile acids from being reabsorbed completely into the enterohepatic circulation, with resulting secretory effects in the colon. Mayo Medical Laboratories recently developed an assay for bile acid in the feces. Until now, a diagnosis of bile acid diarrhea has been provisional and treatment has been empiric.

Medication intolerance

A small percentage of patients develop a hypersensitivity to medications such as sulfasalazine and mesalamine derivatives, leading to a paradoxical worsening of colitis symptoms.

The next steps

All patients with new or worsening symptoms need immediate evaluation. Those without signs of inflammation are not considered refractory and should be investigated for the conditions discussed above. For patients with disease activity, the next step is to consider adjusting the medication dose when possible. If there is an incomplete or lost response, drug and antibody levels should be checked just before the next dose.

"If the drug level is low and the patient doesn't have antibodies, then we need to increase the dose of the anti-tumor necrosis factor (anti-TNF) agent. If the patient already has antibodies, then it's fruitless to keep giving higher doses; we need to switch drugs," Dr. Loftus says. "Even though anti-TNF agents are arguably the most effective class of medications for IBD, only 70 to 80 percent of people, at most, respond initially, and many of those patients lose their response over time, so switching to drugs targeting different pathways in the inflammatory process, such as the leukocyte adhesion blocker vedolizumab, is indicated."

If anti-TNF agents and leukocyte trafficking inhibitors are ineffective, unapproved medications should be considered. One emerging drug receiving considerable attention is ustekinumab, a human monoclonal antibody that targets the p40 subunit of interleukin-23 and interleukin-12, preventing them from binding to receptors on T cells and natural killer cells. Originally developed to treat psoriasis and psoriatic arthritis, ustekinumab has a good safety profile and has shown promise for treatment of Crohn's disease (CD). It is currently used off-label for refractory CD, and depending on the results of phase 3 trials, Food and Drug Administration approval for Crohn's disease is expected in 2016 or 2017.

Although the growing diversity of novel IBD agents is encouraging, Dr. Loftus says it remains critically important to explore whether symptoms are related to active IBD before prescribing new medications. "First and foremost is separating patients who have inflammation from those who don't. Then, if you adjust the dosage of medication in patients with inflammation, the pool of refractory cases gets smaller. It gets smaller still when you try some of the newer drugs with different mechanisms of action," he says.

He points to the evolving concept — borrowed from rheumatology — of treat to target. "We need a target in IBD, which is some measure of inflammation. We then can assess the inflammation, institute a new therapy, and at some fixed point in time — say, six to eight months — reassess it. If there is still inflammation, even if symptoms are better, we keep adjusting therapy until the inflammation resolves. Retrospective studies have shown that this approach, with optimized treatment, can improve mucosal healing rates up to 70 percent. And if we can get that much mucosal healing, that means less surgery, fewer hospitalizations and a better quality of life."